In silico studies on 2-substituted phenol quinazoline derivatives as RET receptor tyrosine kinase antagonists

Abstract

Rearranged during transfection is a transmembrane receptor tyrosine kinase. It is involved in medullary thyroid cancer and lung adenocarcinoma in humans. In this work, molecular docking and three-dimensional quantitative structure–activity relationship studies were performed on recently reported series of two-substituted phenol quinazoline derivatives as rearranged during transfection inhibitors. Docking study identified key active site residues such as Ala807, Lys758, Leu802, Leu730, Tyr806, Ala756, Val804, Asp892, and Glu775 that participate in the inhibition of rearranged during transfection. A reasonable comparative molecular field analysis (q 2 = 0.592, optimal number of components = 4, r 2 = 0.921) and comparative molecular similarity indices analysis (q 2 = 0.580, optimal number of components = 6, r 2 = 0.963) models were generated in three-dimensional quantitative structure–activity relationship study. Various validation techniques such as external test set validation, bootstrapping analysis, and progressive scrambling were carried out to check the predictive ability of the obtained models. The validated models resulted in acceptable statistical values and proved to be predictive and robust. comparative molecular similarity indices analysis model was selected as the final model based on the reasonable statistical values of q 2, r 2, standard error of estimate, and r 2 pred. The contour maps analysis of comparative molecular similarity indices analysis model revealed the favorable regions to enhance the inhibitory activity of compounds. R1 and R4 positions were favorable for bulky substitution. Hydrophilic and negative substitutions at R5 position were favorable. Thus results of our study can provide insights in the designing potent and selective rearranged during transfection kinase inhibitors.